1. Technical Field
The invention relates to an improved process for the preparation of acyclic compounds useful as agents for the treatment of hepatitis C viral (HCV) infections.
2. Background Information
The compounds of the following formula (I) and methods for their preparation are disclosed in the following patent publications: WO 00/09543; U.S. Pat. No. 6,323,180 B1; and U.S. Patent Application Publication No. 2005/0020503 A1:
wherein Het is a five-, six- or seven-membered saturated or unsaturated heterocycle containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur; said heterocycle being substituted with R1 at any available position on the heterocycle;R1 is R20, —NR22COR20, —NR22COOR20—NR22R21 and —NR22CONR21R23, whereinR20 is selected from (C1-8)alkyl, (C3-7)cycloalkyl and (C3-7)cycloalkyl(C1-4)alkyl-, wherein said cycloalkyl or cycloalkylalkyl may be mono-, di- or tri-substituted with (C1-3)alkyl;R21 is H or has one of the meanings of R20 as defined above,R22 and R23 are independently selected from H and methyl,Alk is a C1-C6 alkyl group;A is O or NH;B is (C1-10)alkyl, (C3-7)cycloalkyl, (C3-7)cycloalkyl(C1-4)alkyl,                a) wherein said cycloalkyl, cycloalkylalkyl may be mono-, di- or tri-substituted with (C1-3)alkyl; and        b) wherein said alkyl, cycloalkyl, cycloalkylalkyl may be mono- or di-substituted with substituents selected from hydroxy and (C1-4)alkoxy; and        c) wherein all said alkyl-groups may be mono-, di- or tri-substituted with halogen; and        d) wherein said cycloalkyl-groups being 4-, 5-, 6- or 7-membered having optionally one (for the 4-, 5, 6, or 7-membered) or two (for the 5-, 6- or 7-membered) —CH2-groups not directly linked to each other replaced by —O— such that the O-atom is linked to the group A via at least two C-atoms;            R2 is (C1-8)alkyl, (C3-7)cycloalkyl or (C3-7)cycloalkyl(C1-3)alkyl, wherein said cycloalkyl groups may be mono-, di- or tri-substituted with (C1-4)alkyl;    R3 is ethyl or vinyl;    RC is hydroxyl, C1-C6 alkoxy or NHSO2RS wherein RS is (C1-6)alkyl, (C3-7)cycloalkyl, (C3-7)cycloalkyl(C1-6)alkyl, phenyl, naphthyl, pyridinyl, phenyl(C1-4)alkyl, naphthyl(C1-4)alkyl or pyridinyl(C1-4)alkyl; all of which optionally being mono-, di- or tri-substituted with substituents selected from halogen, hydroxy, cyano, (C1-4)alkyl, (C1-6)alkoxy, —CO—NH2, —CO—NH(C1-4-alkyl), —CO—N(C1-4-alkyl)2, —NH2, —NH(C1-4-alkyl) and —N(C1-4-alkyl)2; and all of which optionally being monosubstituted with nitro;            or Rs can be further selected from: —NH(C1-6alkyl), N(C1-6alkyl)2, -Het,        
or a pharmaceutically acceptable salt or ester thereof.
The compounds of formula (I) are disclosed in the above-mentioned patent documents as being active agents for the treatment of hepatitis C virus (HCV) infections. The methods disclosed for the preparation of these compounds included many synthetic steps and were extremely linear, in that groups were built up sequentially in small increments, rather than synthesizing large fragments and bringing them together (convergency). The problem addressed by the present invention is to provide highly convergent processes which allow for the manufacture of these compounds with a minimum number of steps and with sufficient overall yield.